The virus that caused the 1918 Spanish flu pandemic that killed more people than World War One was so deadly because it triggered an uncontrolled immune system response, scientists say.

About 50 million people died in the pandemic, the worst in modern history, but why it was so lethal has been a mystery.

By infecting macaque monkeys with a reconstructed version of the 1918 virus, researchers have uncovered a clue about the virus that could help to reduce the impact of future influenza pandemics.

They found the virus replicated quickly and unleashed an excessive immune system response in the macaques that destroyed the lungs in a matter of days.

"Instead of protecting the individuals that were infected with the high pathogenic virus, the immune response is actually contributing to the lethality of the virus," says Professor Michael Katze, of the University of Washington in Seattle.

Katze and his international colleagues believe the unusual immune system reaction increased the virulence of the virus in the macaques and in the victims of the Spanish flu pandemic.

"It is very important for us to understand why the virus was so lethal and that is why we did this research," says Professor Yoshihiro Kawaoka who heads the research team.

Similarities to H5N1

The scientists say their findings, which are reported today in the journal Nature, suggest early interventions targeting the immune system response against infection could help to limit the number of deaths that could be caused by future pandemics.

The response in the macaques was similar to what scientists had observed in an earlier study when they infected mice with a reconstructed 1918 virus.

It activated immune cells which attacked the respiratory system causing serious lung damage and death.

"Our analysis revealed potential mechanisms of virulence, which we hope will help us develop novel antiviral strategies to both outwit the virus and moderate the host immune response," Katze adds.

Scientists fear the H5N1 bird flu virus that has killed 161 people and infected 268 since 2003 could spark a pandemic if it becomes highly infectious in humans.

Healthy victims

Unlike other flu viruses that afflict mainly the elderly and children, the Spanish flu pandemic struck young adults and people without immune system problems.

"The H5N1 virus can also cause very serious disease and it appears to do this in a way that is quite similar to the 1918 virus," says Dr Darwyn Kobasa of the Public Health Agency of Canada and lead author of the study.

"A greater understanding of the viruses that caused past pandemics will help us predict what we might expect and how to plan and use our knowledge and resources to reduce the impact of a new pandemic," he adds.